Chetan RastogiM.Pharm 1st Year Pharmacology

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Psychosis Psychosis refers to a variety of mental disorders

characterized by one or more of the following

symptoms:

diminished and distorted capacity to process

information and draw logical conclusions.

hallucinations, delusions, marked loosening of

associations.

disorganized behavior, and aggression or

violence.2

Psychosis:

Psychosis can be broadlyCategorized in to 2 groups:1 ORGANIC2 FUNCTIONAL

Psychosis

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1.Acute and chronic organic brain syndromes (cognitive disorders) such as, Delirium and dementia, prominent features of confusion, disorientation, defective memory and disorganized behavior.

2.Functional disorders such as, memory and orientation mostly retained by emotion, thought, reasoning and behavior are altered.

3.Schizophrenia (split mind) i.e. splitting of perception and interpretation from reality- hallucination, inability to think coherently. Schizophrenia is often described in terms of positive or negative (deficit) symptoms..

4.Paranoid state i.e. fixed delusions (false beliefs) and loss of insight in to abnormality.

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Schizophrenia

It is a thought disorder.The disorder is characterized by a

divorcement from reality in the mind of the person (psychosis).

It may involved visual and auditory hallucinations, delusions, intense suspicion, feelings of persecution or control by external forces (paranoia), depersonalization, and there is attachment of excessive personal significance to daily events, called “ideas of reference”.

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Schizophrenia

Positive Symptoms

Hallucinations, delusions, paranoia, ideas of reference.

Negative Symptoms

Apathy, social withdrawal, anhedonia, emotional

blunting, Poor speech –Cognitive impairment Poor speech –Cognitive impairment ,

extreme inattentiveness or lack of motivation to

interact with the environment.

These symptoms are progressive and non-responsive to

medication.6

Psychosis Producing Drugs

1) Levodopa

2) CNS stimulants

a) Cocaine

b) Amphetamines

c) Khat, cathinone, methcathinone

3) Apomorphine

4) Phencyclidine

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Dopamine Theory of Schizophrenia

Dopamine Correlates:• Antipsychotics reduce dopamine synaptic activity.• These drugs produce Parkinson-like symptoms.• Drugs that increase DA in the limbic system cause

psychosis.• Drugs that reduce DA in the limbic system

(postsynaptic D2 antagonists) reduce psychosis.• Increased DA receptor density (Post-mortem, PET).• Changes in amount of homovanillic acid (HVA), a

DA metabolite, in plasma, urine, and CSF.

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Dopamine Theory of Schizophrenia

Evidence against the hypothesisAntipsychotics are only partially effective in

most (70%) and ineffective for some patients.Phencyclidine, an NMDA receptor antagonist,

produces more schizophrenia-like symptoms in non-schizophrenic subjects than DA agonists.

Atypical antipsychotics have low affinity for D2 receptors.

Focus is broader now and research is geared to produce drugs with less extrapyramidal effects.

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Dopamine System

There are four major pathways for the dopaminergic system in the brain:

I. The Nigro-Stiatal Pathway.II. The Mesolimbic Pathway.III. The Mesocortical Pathway.IV. The Tuberoinfundibular Pathway.

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Catecholamines

Tyrosine Tyrosine hydroxylase

L-Dopa Dopa decarboxylase

Dopamine (DA) Dopamine

hydroxylase

Norepinephrine (NE)(Noradrenaline)

Phenylethanolamine-

-N-methyltransferase

Epinephrine (EPI)(Adrenaline)

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Dopamine Synapse

DA

L-DOPA

Tyrosine

Dopamine SystemDOPAMINE RECEPTORS

There are at least five subtypes of receptors: Receptor

D1D2D3D4D5

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Dopamine System DOPAMINE RECEPTORS

Receptor 2o Messenger System D1 cAMP D2 cAMP,K+

ch.,Ca2+ch. D3 cAMP,K+

ch.,Ca2+ch. D4 cAMP D5 cAMP

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Dopamine Reuptake System

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ANTIPSYCHOTICS

Antipsychotic drugs are alsoknown as Neuroleptics, Ataractic,Major Tranquilizer and Anti-Schizophrenic drugs. A firstgeneration of antipsychotics,known as Typical antipsychotics,was discovered in the 1950s. Mostof the drugs in the secondgeneration, known as Atypical

antipsychotics,have been developed more recently.

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CLASSIFICATION

A.Typical Antipsychotics: (traditional/older)traditional/older)

1. Phenothiazines:

a. Aliphatic side chain: Chlorpromazine, Triflupromazine

b. Piperidine side chain: Thioridazine

c. Piperazine side chain: Trifluoperazine, perphenazine

Fluphenazine

 

2. Butyrophenones: Haloperidol, Trifluperidol, Penfluridol,

droperidol, domperidone

 

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3. Thioxanthenes: Flupenthixol

  4. Other heterocyclics: Pimozide, Loxapine,

molindone, sulpiride, amisulpiride, penfluridol, Remoxipride, metoclopramide

 B. Atypical/newer antipsychotics: Clozapine, Risperidone, Olanzapine, Quetiapine, Aripiprazole, Ziprasidone,

paloparidone

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Low potencyLow potency High potencyHigh potency NEWERNEWER

ChlorpromaziChlorpromazinene

ThioridazineThioridazine

ThiothixeneThiothixene

ExtrapyramidExtrapyramidal symptoms al symptoms LESSLESS

Anti-ch MOREAnti-ch MORE

Haloperidol, Haloperidol, Fluphenazine,TrFluphenazine,Trifluoperazine,Peifluoperazine,Perphennazine, rphennazine, PimozidePimozide

Extrapyramidal-Extrapyramidal-MORE,MORE,

AntiCh LESSAntiCh LESS

ClozapineClozapine

OlanzapineOlanzapine

QuetiapineQuetiapine

AripiprazoleAripiprazole

RisperidoneRisperidone

ZiprasidoneZiprasidone

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Traditional Vs. AtypicalTraditional Vs. Atypical Mainly DAMainly DAMainly D2Mainly D2Treat mostly Treat mostly

POSITIVE symptomsPOSITIVE symptomsMore adverse effectsMore adverse effectsLess useful in Less useful in

refractory diseaserefractory disease

DA and 5HTDA and 5HTD2+D4+5HTD2+D4+5HTTreat POSITIVE and Treat POSITIVE and

NEGATIVENEGATIVE symptomssymptoms

Lesser adverse Lesser adverse effectseffects

Useful in refractory Useful in refractory diseasedisease

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Mechanism of Action:

-Antipsychotic blocks D₂receptors in the brain'sDopaminergic pathway.

-Some also block or partiallyblock serotonin receptors(particularly 5HT2A, C and

5HT1A receptors)

 -But antipsychotic drugs can

alsoblock wide range of receptortargets.

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In the Mesolimbic- Mesocortical and Nigrostriatal pathway Antipsychotic blocks:

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In the Tuberoinfundibular pathway Antipsychotics block:

Dopamine released at this site regulates the secretion of prolactinfrom anterior the pituitary gland.Antipsychotics blocks D₂ receptor at this site.

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Antipsychotic blocks D₂ receptors Some also block or partially block serotonin receptors

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Pharmacology of Antipsychotics:Typical Antipsychotics

Phenothiazine

Absorption

Concentration

Metabolism

Vd Dose

Chlorpromazine (CPZ)

More consistent effect in IV and IM administration

Highly bound to plasma and tissue protein

Metabolized in liver by CYP2D6 enzyme

Large 20 L/kg

Acute single dose lasts 6-8 hours t⅟₂ is 18-30 hrs

Triflupromazine

More potent than CPZ

-- -- --

Thioridazine Low potency with anticholinergic action

-- -- --

Trifluoperazine, Fluphenazine

High potency with Autonomic action

-- -- -- Depot IM inj every 2-4 weeks (25mg/ml )

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Butyrophenones Potency t⅟₂ Dose

Haloperidol Potent antipsychotic Produces few autonomic effects

24 hours. --

Trifluperidol Similar toHaloperidol but slightly more potent

-- --

Penfluridol Exceptional long acting neuroleptic, used for chronic Schizophrenia, affective withdrawl and social mal-adjustment

-- 20-60 mg , once weekly

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Thioxanthenes

Flupenthixol Less sedative than CPZ, indicated for Schizophrenia and other Psychoses.

Other heterocyclics

t⅟₂

Pimozide Specific DA antagonist with little adrenergic or cholinergic blocking activity. Used in Gilles de la Tourett’s syndrome and ticks. Long Duration of action.

48-60 hrs. (after single dose)

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Atypical Antisychotic drugs

These are newer 2nd

Generation antipsychoticsthat have weak D₂

receptorblocking but potent 5-HT₂antagonistic activity. TheyMay improve the impairedCognitive function inpsychotics.

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Atypical Blocking activity Metabolism(Enzyme)

t⅟₂ and Dose

Clozapine A very potent antipsychotic

D₂, D₄, 5HT₂, α receptors

By CYP3A4 t⅟₂ - 12 hours

Risperidone

-- Combination of D₂+5HT₂ , High affinity for α₁, α₂ and H₁ receptors

-- Dose - Low dose <6 mg/day

Olanzapine Potent antipsychotic Broader spectrum of efficacy

Monoaminergic (D₂, 5HT₂, α₁, α₂) as well as muscarinic and H₁ receptors

By CYP1A2 and Glucuronyl transferase

t⅟₂ - 24-30 hours

Quetiapine New short- acting antipsychotic

5HT₁А, 5HT₂, D₂, α₁, α₂ and H₁ receptor

By CYP3A4 --

Aripiprazole

Unique antipsychotic which is partial agonist at D₂ and 5HT₁А

5HT₂ By CYP2D6 and CYP3A4

t⅟₂ - 3days

Ziprasidone

Latest antipsychotic , moderately potent inhibitor.

Combination D₂+5HT₂A/₂C +H₁ + α₁,Na reuptake

-- t⅟₂ - 8 hours

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ADVERSE EFFECTS OF TYPICAL NEUROLEPTICSAnticholinergic (antimuscarinic) side

effects:Dry mouth, blurred vision, tachycardia,

constipation, urinary retention, impotence

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ADVERSE EFFECTS OF TYPICAL NEUROLEPTICSAntiadrenergic (Alpha-1) side effects:

Orthostatic hypotension w/ reflex tachycardia

sedation

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ADVERSE EFFECTS OF TYPICAL NEUROLEPTICSAntihistamine effect: sedation, weight gain

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KEY CONCEPT: DOPAMINE-2 RECEPTOR BLOCKADE IN THE BASAL GANGLIA RESULTS IN EXTRAPYRAMIDAL MOTOR SIDE EFFECTS (EPS).

DYSTONIANEUROLEPTIC MALIGNANT SYNDROMEPARKINSONISMTARDIVE DYSKINESIAAKATHISIA

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ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS (Continued)Increased prolactin secretion (common with all;

from dopamine blockade)Weight gain (common, antihistamine effect?)Photosensitivity (v. common w/ phenothiazines)Lowered seizure threshold (common with all)Leucopenia , agranulocytosis (rare; w/

phenothiazines)Retinal pigmentopathy (rare; w/ phenothiazines)

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ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS (Continued)

Chlorpromazine and thioridazine produce marked autonomic side effects and sedation; EPS tend to be weak (thioridazine) or moderate (chlorpromazine).

Haloperidol, thiothixene and fluphenazine produce weak autonomic and sedative effects, but EPS are marked.

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MANAGEMENT OF EPSDystonia and parkinsonism: anticholinergic

antiparkinson drugs

Neuroleptic malignant syndrome: muscle relaxants, DA agonists, supportive

Akathisia: benzodiazepines, propranolol

Tardive dyskinesia: increase neuroleptic dose; switch to clozapine

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